(4R,5S)-4-methyl-5-phenyl-1,3-oxazolidin-2-one

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 226 mg of 3-isopropylthiopropionic acid was dissolved in 1.5 ml of dry dichloromethane. 0.22 ml (1.0 eq) of triethylamine was added thereto, and then the mixture was cooled with ice. 0.19 ml of pivaloyl chloride was added thereto under stirring to obtain a gelled reaction solution. The reaction solution was stirred at 10° C. for 10 minutes and then cooled with ice. A dichloromethane solution of lithium amide prepared from 270 mg of (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone and 0.96 ml of 1.5M n-butyl lithium was prepared, and the solution was added to the previous reaction solution under cooling with ice. The mixture was stirred at room temperature overnight, and then the reaction solution was diluted with 20 ml of chloroform. After washing with 15 ml of a 4% sodium hydrogencarbonate aqueous solution, the chloroform solution was dried over anhydrous magnesium sulfate. The chloroform solution was concentrated under reduced pressure, and then purified by silica gel column chromatography (n-hexane/ethyl acetate=6/1) to obtain 240 mg of (4R,5S)-3-(3-isopropylthiopropionyl)-4-methyl-5-phenyl-2-oxazolidinone as colorless transparent syrup (yield: 51%). the mixture was cooled with ice to obtain a gelled reaction solution The reaction solution was stirred at 10° C. for 10 minutes cooled with ice was prepared the solution was added to the previous reaction solution under cooling with ice The mixture was stirred at room temperature overnight After washing with 15 ml of a 4% sodium hydrogencarbonate aqueous solution the chloroform solution was dried over anhydrous magnesium sulfate The chloroform solution was concentrated under reduced pressure purified by silica gel column chromatography (n-hexane/ethyl acetate=6/1)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mechanically stirred solution of the resultant compound from Example 64 (10 g, 56.4 mmol) in dry THF (200 ml) under an atmosphere of nitrogen was treated with n-butyl-lithium in hexanes (1.05 equiv, 22.6 ml, 56.4 mmol, 2.5M) at -78° C. After stirring for an additional 20 min at -78° C., hydrocinnamoyl chloride (9.4 ml, 62 mmol, 1.1 equiv) was added and the reaction was allowed to warm to room temperature with stirring over 2 h. The clear reaction mixture was poured into 100 ml of saturated NH4Cl. The organic layer was removed and the resulting aqueous layer extracted three times with dichloromethane. The combined organic extracts were washed once with brine, dried (anhydrous sodium sulfate), filtered, and concentrated under reduced pressure to afford a crude solid. This material was recrystallized from hot ethyl acetate/hexane at 0°-5° C. overnight. First crop yielded 12.9 g, mp 99°-100° C. Second crop afforded 3.6 g. Total yield 16.5 g (95%). to warm to room temperature with stirring over 2 h The organic layer was removed the resulting aqueous layer extracted three times with dichloromethane The combined organic extracts were washed once with brine dried (anhydrous sodium sulfate) filtered concentrated under reduced pressure to afford a crude solid This material was recrystallized from hot ethyl acetate/hexane at 0°-5° C. overnight First crop yielded 12.9 g, mp 99°-100° C Second crop afforded 3.6 g

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask was charged with 4.17 g (19.6 mmol) of (R)-6-cyclohexyl-4-methyl-hexanoic acid, 40 mL of THF, and 8.56 mL (61.4 mmol) of triethylamine. The mixture was cooled in a 0° C. bath, and 2.41 mL (19.6 mmol) of pivaloyl chloride was added. The mixture was stirred for 1 h at 0° C. Then 2.79 g (16.4 mmol) of (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone and 0.823 g (19.6 mmol) of lithium chloride were added as solids. The mixture was allowed to warm to room temperature and stirred overnight. The resulting solids were filtered off. The solvent was stripped under reduce pressure, and the residue was purified by column chromatography (eluent: 4:1 hexanes/ethyl acetate) to give 6.09 g (quant.) of a clear oil: 1H NMR (400 MHz, CDCl3) δ ppm 0.89 (m, 8 H) 1.16 (m, 6 H) 1.68 (m, 9 H) 2.87 (m, 1 H) 2.99 (m, 1 H) 4.76 (qd, J=6.83, 6.59 Hz, 1 H) 5.66 (d, J=7.32 Hz, 1 H) 7.30 (m, 2 H) 7.40 (m, 3 H). MS (APCl) m+1/z=372. to warm to room temperature stirred overnight The resulting solids were filtered off the residue was purified by column chromatography (eluent: 4:1 hexanes/ethyl acetate) to give 6.09 g (quant.) of a clear oil

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Lithium aluminium hydride (10.26 g) was added to a stirred solution of (4R,5S)-4-methyl-3-((2R)-2-methyl-4,4,4-trifluorobutyryl)-5-phenyl-2-oxazolidinone (28 g) in dry diethyl ether (200 mL) at -20° C. under an inert atmosphere, then the mixture was warmed to 0° C. After 2h at 0° C., water (10.27 mL), 10% w/v sodium hydroxide (10.27 mL) and water (31 mL) were added, and the mixture was stirred 20 min. The salts were filtered and washed with distilled diethyl ether. The diethyl ether solution was dried (K2CO3) and diluted with pentane. This resulted in precipitation of recovered (4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone which was isolated by filtration. Concentration of the filtrate by distillation afforded several fractions. The first fractions (bath temperature to 60° C. were pentane and diethyl ether; a second set of fractions (bath temperature 60° C. to 100° C.) was 12 g of a oil that was a 40:60 mixture of (R)-2-methyl-4,4,4-trifluorobutan-1-ol (calculated as 4.8 g alcohol) and diethyl ether by NMR. Warming the remaining tarry residue (bath temperature 85° C.) under vacuum (13,330 Pa) afforded an additional 7.2 g of (R)-2-methyl-4,4,4-trifluorobutan-1-ol (total yield, 12.0 g, 94%); partial NMR (300 MHz, CDCl3 -D2O shake); 1.06(d,3H,CH3), 1.41(br t,1H,OH), 1.86-2.07(m,2H,CH(CH3) plus one CF3CH2), 2.31-2.42(m,1H, one CF3CH2), 3.49(dd,1H, one CH2OH), 3.58(dd,1H, one CH2OH). at 0° C. were added The salts were filtered washed with distilled diethyl ether The diethyl ether solution was dried (K2CO3) diluted with pentane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of (4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone (3.22 g) and tetrahydrofuran (35 ml) at -70° C., under nitrogen was added 1.625M n-butyllithium (12.31 mL) and the mixture was stirred for 15 min. 2-Methyl-4,4,4-trifluorobutyryl chloride (3.5 g) was added to the reaction mixture which was stirred for 15 min at -70° C. and then at 0° C. for 1 hour. The reaction was quenched with ammonium chloride and extracted with ethyl acetate. The organic phase was washed (saturated NaHCO3, brine) and dried (MgSO4). Evaporation and flash chromatography, eluting with 5:95 then 1:9 ethyl acetate:petroelum ether, afforded the two diastereomeric products. Recrystallization from hexane at 20° C. gave (4R,5S)-4-methyl-3-((2R)-2-methyl-4,4,4-trifluorobutyryl)-5-phenyl-2-oxazolidinone (2.376 g, 42%) as colorless needles; mp 72.5°-73.5° C.; TLC, Rf =0.43, 1:9 ethyl acetate:petroleum ether; MS(CI): 316 (M+H). was stirred for 15 min at -70° C. at 0° C. for 1 hour The reaction was quenched with ammonium chloride extracted with ethyl acetate The organic phase was washed (saturated NaHCO3, brine) dried (MgSO4) Evaporation and flash chromatography eluting with 5:95 1:9 ethyl acetate:petroelum ether, afforded the two diastereomeric products Recrystallization from hexane at 20° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 226 mg of 3-isopropylthiopropionic acid was dissolved in 1.5 ml of dry dichloromethane. 0.22 ml (L.0 eq) of triethylamine was added thereto, and then the mixture was cooled with ice. 0.19 ml of pivaloyl chloride was added thereto under stirring to obtain a gelled reaction solution. The reaction solution was stirred at 10° C. for 10 minutes and then cooled with ice. A dichloromethane solution of lithium amide prepared from 270 mg of (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone and 0.96 ml of 1.5M n-butyl lithium was prepared, and the solution was added to the previous reaction solution under cooling with ice. The mixture was stirred at room temperature overnight, and then the reaction solution was diluted with 20 ml of chloroform. After washing with 15 ml of a 4% sodium hydrogencarbonate aqueous solution, the chloroform solution was dried over anhydrous magnesium sulfate. The chloroform solution was concentrated under reduced pressure, and then purified by silica gel column chromatography (n-hexane/ethyl acetate=6/1) to obtain 240 mg of (4R,5S)-3-(3-isopropylthiopropionyi)-4-methyl-5-phenyl-2-oxazolidinone as colorless transparent syrup (yield: 51%). the mixture was cooled with ice to obtain a gelled reaction solution The reaction solution was stirred at 10° C. for 10 minutes cooled with ice was prepared the solution was added to the previous reaction solution under cooling with ice The mixture was stirred at room temperature overnight After washing with 15 ml of a 4% sodium hydrogencarbonate aqueous solution the chloroform solution was dried over anhydrous magnesium sulfate The chloroform solution was concentrated under reduced pressure purified by silica gel column chromatography (n-hexane/ethyl acetate=6/1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (4R,5S)-3-(1′-oxopentyl)-4-methyl-5-phenyl-2-oxazolidinone was synthesized from (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone and valeroyl chloride by the same procedure as (4S)-3-(1′-oxopentyl)-4-benzyl-2-oxazolidinone. The product (29.55 g) was obtained in 84% yield.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (4R,5S)-3-(1′-oxopentyl)-4-methyl-5-phenyl-2-oxazolidinone was synthesized from (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone and valeroyl chloride by the same procedure as (4S)-3-(1′-oxopentyl)-4-benzyl-2-oxazolidinone. The product (29.55 g) was obtained in 84% yield.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (4R,5S)-3-(1′-oxopentyl)-4-methyl-5-phenyl-2-oxazolidinone was synthesized from (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone and valeroyl chloride by the same procedure as (4S)-3-(1′-oxopentyl)-4-benzyl-2-oxazolidinone. The product (29.55 g) was obtained in 84% yield.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 226 mg of 3-isopropylthiopropionic acid was dissolved in 1.5 ml of dry dichloromethane. 0.22 ml (1.0 eq) of triethylamine was added thereto, and then the mixture was cooled with ice. 0.19 ml of pivaloyl chloride was added thereto under stirring to obtain a gelled reaction solution. The reaction solution was stirred at 10° C. for 10 minutes and then cooled with ice. A dichloromethane solution of lithium amide prepared from 270 mg of (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone and 0.96 ml of 1.5M n-butyl lithium was prepared, and the solution was added to the previous reaction solution under cooling with ice. The mixture was stirred at room temperature overnight, and then the reaction solution was diluted with 20 ml of chloroform. After washing with 15 ml of a 4% sodium hydrogencarbonate aqueous solution, the chloroform solution was dried over anhydrous magnesium sulfate. The chloroform solution was concentrated under reduced pressure, and then purified by silica gel column chromatography (n-hexane/ethyl acetate=6/1) to obtain 240 mg of (4R,5S)-3-(3-isopropylthiopropionyl)-4-methyl-5-phenyl-2-oxazolidinone as colorless transparent syrup (yield: 51%). the mixture was cooled with ice to obtain a gelled reaction solution The reaction solution was stirred at 10° C. for 10 minutes cooled with ice was prepared the solution was added to the previous reaction solution under cooling with ice The mixture was stirred at room temperature overnight After washing with 15 ml of a 4% sodium hydrogencarbonate aqueous solution the chloroform solution was dried over anhydrous magnesium sulfate The chloroform solution was concentrated under reduced pressure purified by silica gel column chromatography (n-hexane/ethyl acetate=6/1)

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 117-ml of a 1.6 molar solution of butyllithium in hexane is added within 30 minutes at −70° C. under nitrogen to a solution of 30.1 g of (4R,5S)-4-methyl-5-phenyloxazolidin-2-one in 500 ml of tetrahydrofuran. Then, a solution of 26.8 g of bromoacetyl chloride in 250 ml of tetrahydrofuran is added in drops, so that the temperature does not exceed −65° C. After 1.75 hours of stirring at −70° C., a saturated ammonium chloride solution is added, followed by 60 ml of a saturated sodium bicarbonate solution, and it is allowed to come to 25° C. After the phases are separated, the aqueous phase is extracted twice with 100 ml of ether each. The combined organic phases are washed with semiconcentrated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum after filtration. The residue that is thus obtained is purified by chromatography on silica gel. With hexane/0–50% ether, 34.8 g of the title compound is obtained as a colorless oil. does not exceed −65° C to come to 25° C After the phases are separated the aqueous phase is extracted twice with 100 ml of ether each The combined organic phases are washed with semiconcentrated sodium chloride solution dried on sodium sulfate concentrated by evaporation in a vacuum after filtration The residue that is thus obtained is purified by chromatography on silica gel

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (4R,5S)-4-Methyl-5-phenyl-oxazolidin-2-one (25.21 g, 142.269 mmol) is dissolved in anhydrous THF (100 mL) and cooled to −78° C. n-Butyl lithium (2.5 M in hexanes, 62.60 mL, 156.5 mmol) is added dropwise over 10 min. The reaction is stirred at −78° C. for 10 min. Phenylacetyl chloride (20.73 mL, 156.5 mmol) is dissolved in anhydrous THF (50 mL) and added dropwise over 10 min. The reaction is stirred at −78° C. for 2 h. The reaction is poured onto brine (300 mL) and extracted with ethyl acetate (2×250 mL). Extracts are combined, dried over anhydrous sodium sulfate, filtered, and concentrated to a yellow oil which solidified upon standing. Therude product is purified by column chromatography over silica eluting with 5→45% ethyl acetate in hexanes to afford (4R,5S)-4-methyl-5-phenyl-3-phenylacetyl-oxazolidin-2-one as a white solid: 1H NMR (400 MHz, DMSO-D6) δ 0.8 (d, J=6.6 Hz, 3 H) 4.2 (m, 2 H) 4.8 (m, 1 H) 5.9 (d, J=7.3 Hz, 1 H) 7.2 (m, 3 H) 7.3 (m, 5 H) 7.4 (m, 2 H); LC/MS 296.2 (M+1), 294.1 (M−1). is added dropwise over 10 min added dropwise over 10 min The reaction is stirred at −78° C. for 2 h The reaction is poured onto brine (300 mL) extracted with ethyl acetate (2×250 mL) dried over anhydrous sodium sulfate filtered concentrated to a yellow oil which Therude product is purified by column chromatography over silica eluting with 5→45% ethyl acetate in hexanes